Preclinical Assessment of [68Ga]Ga-Cell Death Indicator (CDI): A Novel hsp90 Ligand for Positron Emission Tomography of Cell Death.

BACKGROUND: 4-(N-(S-glutathionylacetyl)amino) phenylarsonous acid (GSAO) when conjugated with a bifunctional chelator 2,2'-(7-(1-carboxy-4-((2,5-dioxopyrrolidin-1-yl)oxy)-4- oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODAGA) (hereafter referred to as Cell Death Indicator [CDI]), enters dead and dying cells and binds to 90kDa heat shock proteins (hsp90). OBJECTIVE: This study assesses stability, biodistribution, imaging, and radiation dosimetry of [68Ga]- Ga-CDI for positron emission tomography (PET). METHODS: Preparation of [68Ga]Ga-CDI was performed as previously described. Product stability and stability in plasma were assessed using high-performance liquid chromatography. Biodistribution and imaging were conducted in ten healthy male Lewis rats at 1 and 2 h following intravenous [68Ga]Ga-CDI injection. Human radiation dosimetry was estimated by extrapolation for a standard reference man and calculated with OLINDA/EXM 1.1. RESULTS: Radiochemical purity of [68Ga]Ga-CDI averaged 93.8% in the product and 86.7% in plasma at 4 h post-synthesis. The highest concentration of [68Ga]Ga-CDI is observed in the kidneys; [68Ga]Ga-CDI is excreted in the urine, and mean retained activity was 32.4% and 21.4% at 1 and 2 h post-injection. Lower concentrations of [68Ga]Ga-CDI were present in the small bowel and liver. PET CT was concordant and additionally demonstrated focal growth plate uptake. The effective dose for [68Ga]Ga-CDI is 2.16E-02 mSv/MBq, and the urinary bladder wall received the highest dose (1.65E-02 mSv/Mbq). CONCLUSION: [68Ga] Ga-CDI is stable and has favourable biodistribution, imaging, and radiation dosimetry for imaging of dead and dying cells. Human studies are underway.

Resistance to Streptococcus iniae and its genetic associations with traits of economic importance in Asian seabass (Lates calcarifer).

Streptococcus iniae is one of the most serious aquatic pathogens, causing significant economic losses in marine and freshwater species, including Asian seabass (Lates calcarifer). Controlling this gram-positive bacterial pathogen has been an issue in aquaculture systems, due to the combined effects of aquaculture intensification and climatic impacts. To date, there have not been any genetic parameter estimates for S. iniae resistance in Asian seabass. The main aim of this study was to examine genetic variation in S. iniae resistance and its genetic correlations with growth and cannibalism in Asian seabass families produced from a breeding programme for high growth in 2016 and 2017. The study included a total of 5,835 individual fish that were offspring of 41 sires and 60 dams (31 half-sib and 34 full-sib families). The experimental fish were challenged by intraperitoneal injection with a volume containing 105  CFU (colony-forming unit)/fish. Resistance to S. iniae was measured as survival rate at 6 hr, 3, 5, 7, 10 and 15 days post-challenge test. There were significant variations in S. iniae resistance among families at different observation periods (ranging from 24.4% to 80%). Restricted maximum-likelihood method and mixed model analysis were applied to estimate heritability for S. iniae resistance. The heritability for S. iniae resistance ranged from 7% to 18% across different statistical models used. The common full-sib effects accounted for 0.1%-2% of the total variation in resistance to S. iniae. Genetic correlations of the S. iniae resistance at 6 hr and 3 days with later post-challenge test periods were low to moderate. However, these estimates for S. iniae resistance between successive measurement times (5, 7, 10 and 15 days) were high and close to 1. The genetic correlations of resistance with body weights at 180, 270 and 360 days post-hatch were not significant as well with cannibalism. It is concluded that there is substantial additive genetic variation in resistance to S. iniae, suggesting there is potential for genetic improvement of Asian seabass for resistance to S. iniae through selective breeding.